Protective Effects of Growth Arrest-Specific Protein 6 (Gas6) on Sepsis-Induced Acute Kidney Injury
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ORIGINAL ARTICLE
Protective Effects of Growth Arrest-Specific Protein 6 (Gas6) on Sepsis-Induced Acute Kidney Injury Long-wang Chen,1 Wei Chen,1 Zhi-qiang Hu,1 Jia-lan Bian,1 Lan Ying,1 Guang-liang Hong,1 Qiao-meng Qiu,1 Guang-ju Zhao,1,2 and Zhong-qiu Lu1,2
Abstract—Acute kidney injury (AKI) is a serious complication of sepsis, which has a high mortality rate. Growth arrest-specific protein 6 (Gas6), the protein product of the growth arrest specific gene 6, has been shown to have an anti-apoptotic effect as well as pro-survival capability. Here, we investigated the effects of Gas6 on sepsis-associated AKI in mice subjected to cecal ligation and puncture (CLP). We found that the administration of rmGas6 significantly reduced serum urea nitrogen and creatinine and improved the survival of septic mice. Furthermore, the renal pathological damage induced by CLP was attenuated by rmGas6 treatment. Finally, rmGas6 reduced the renal tissue apoptotic index and the expression of Bax, while it upregulated the expression of Bcl-2. The data suggest that rmGas6 might be used as a potential therapeutic agent for sepsis-induced AKI. KEY WORDS: gas6; acute kidney injury; sepsis; apoptosis.
INTRODUCTION Sepsis is one of the most frequent causes of mortality in intensive care units (ICU), resulting in excessive tissue injury and death in approximately 30 to 50 % of patients [1]. Among septic patients, 42.1 % had concomitant acute kidney injury (AKI) (septic AKI) [2]. The mortality rate of sepsis-induced AKI is more than 70 % [3]. Despite advances in management strategies, the outcome of AKI in patients with sepsis remains poor. Thus, the development of new agents is of paramount importance in sepsis therapy. Gas6, a member of the vitamin K-dependent protein family, was initially described as a protein expressed during growth arrest [4]. Various cell types express Gas6, including endothelial cells, the vascular smooth muscle, 1
Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China 2 To whom correspondence should be addressed at Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China. E-mails: [email protected]; [email protected]
leukocytes, and platelets. Gas6 plays a role in leukocyte sequestration and migration, platelet aggregation and hematopoiesis, proliferation, apoptosis, and phagocytosis and is generally associated with conditions of injury, inflammation, and repair [5]. Gas6 is the ligand for the TAM family of receptors, which is composed of three members: Tyro3, Axl, and Mer [6, 7]. The binding of Gas6 to Axl induces Axl phosphorylation and activation of the PI3 kinase/Akt pathway, which has pro-survival and antiapoptotic effects [8]. During TNF-α-mediated cytotoxicity of human umbilical vein endothelial cells, Gas6 is able to protect against apoptosis and prolong survival when growth factors are depleted [9–11]. In hepatic ischemia/ reperfusion injury, Gas6 is found to be prote
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